Guidelines for genetic testing of muscle and neuromuscular junction disorders

Abstract

Despite recent advances in the understanding of inherited muscle and neuromuscular junction diseases, as well as the advent of a wide range of genetic tests, patients continue to face delays in diagnosis of sometimes treatable disorders. These guidelines outline an approach to genetic testing in such disorders. Initially, a patient's phenotype is evaluated to identify myopathies requiring directed testing, including myotonic dystrophies, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, mitochondrial myopathies, dystrophinopathies, and oculopharyngodistal myopathy. Initial investigation in the remaining patients is generally a comprehensive gene panel by next-generation sequencing. Broad panels have a higher diagnostic yield and can be cost-effective. Due to extensive phenotypic overlap and treatment implications, genes responsible for congenital myasthenic syndromes should be included when evaluating myopathy patients. For patients whose initial genetic testing is negative or inconclusive, phenotypic re-evaluation is warranted, along with consideration of genes and variants not included initially, as well as their acquired mimickers.

The utility of electrodiagnostic testing in unprovoked rhabdomyolysis in the era of next‐generation sequencing

“…However, should the genetic panel fails to detect pathogenic variants, or if a mitochondrial myopathy is initially suspected, then EDX testing should be considered as it could reveal an underlying myopathy, help target muscle biopsy site, and guide further evaluation. If a mitochondrial myopathy is present, a muscle biopsy would provide affected tissue for high‐yield diagnostic mitochondrial DNA sequencing 28–30 …”

Dyslipidemia in Muscular Dystrophy: A Systematic Review and Meta-Analysis

“…Potentially relevant studies were subsequently screened by full text reading, with any possible conflicts resolved by discussion and reaching a consensus. Studies included in the systematic review met the following inclusion criteria: a) Diagnosis of MD based on guidelines for genetic testing of muscle and neuromuscular junction disorders [ 27 ], or any other definition claimed by original studies’ authors; b) At least one of the following plasma/serum levels of lipids was reported: triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL); c) Same data in non-muscular dystrophic population were reported; d) English only. Studies were excluded if: a) No clear diagnosis of MD was reported; b) Animal or in vitro studies; c) No report or measures of plasma/serum levels of lipids was reported; d) Absence of non-MD ‘healthy’ control lipid values, which is a requirement for meta-analysis.…”

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

“…repeats, highly homologous regions, and regions of high and low GC content ( 37 ). Common neuromuscular repeat expansion disorders not detectable via NGS include myotonic dystrophy 1 and 2, facioscapulohumeral muscular dystrophy 1 (FSHD1), oculopharyngeal muscular dystrophy (OPMD), oculopharyngodistal myopathies ( 52 ), and C9orf72 -related amyotrophic lateral sclerosis. When ordering a gene panel, it is thus essential to check if the gene panel included the appropriate methodology to cover these special conditions.…”

“…Eg. in a patient with muscle weakness, genes for Pompe Disease, Congenital Myasthenic Syndrome ( 52 ), and Spinal Muscular Atrophy ( 86 ) should be included to avoid missing a potentially treatable disease.…”